[ CAS No. 155542-33-9 ] {[proInfo.proName]}

Name: 155542-33-9|Boc-D-Asp(OtBu)-OH|97%
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SKU: A170283
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Quality Control of [ 155542-33-9 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 155542-33-9 ]

SDS Specification

Alternatived Products of [ 155542-33-9 ]

Product Details of [ 155542-33-9 ]

CAS No. :	155542-33-9	MDL No. :	MFCD01861313
Formula :	C₁₃H₂₃NO₆	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	-
M.W :	289.32	Pubchem ID :	-
Synonyms :

Calculated chemistry of [ 155542-33-9 ]

Physicochemical Properties

Num. heavy atoms :	20
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.77
Num. rotatable bonds :	9
Num. H-bond acceptors :	6.0
Num. H-bond donors :	2.0
Molar Refractivity :	72.21
TPSA :	101.93 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-7.09 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.25
Log Po/w (XLOGP3) :	1.37
Log Po/w (WLOGP) :	1.7
Log Po/w (MLOGP) :	1.08
Log Po/w (SILICOS-IT) :	0.8
Consensus Log Po/w :	1.44

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.56

Water Solubility

Log S (ESOL) :	-1.9
Solubility :	3.62 mg/ml ; 0.0125 mol/l
Class :	Very soluble
Log S (Ali) :	-3.11
Solubility :	0.223 mg/ml ; 0.00077 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-1.55
Solubility :	8.12 mg/ml ; 0.0281 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	3.44

Safety of [ 155542-33-9 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 155542-33-9 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Upstream synthesis route of [ 155542-33-9 ]
Downstream synthetic route of [ 155542-33-9 ]

[ 155542-33-9 ] Synthesis Path-Upstream 1~1

1
[ 24424-99-5 ]
[ 64960-75-4 ]
[ 155542-33-9 ]

Yield	Reaction Conditions	Operation in experiment
99%	Stage #1: at 0℃; for 0.0833333 h; Stage #2: With sodium carbonate In tetrahydrofuran; water at 20℃; for 24 h;	General procedure: L-Aspartic acid 4-tert-butyl ester 4a (1.89 g, 10 mmol) was dissolved in a mixture of tetrahydrofuran (20 mL) and water (12 mL) at 0°C. After stirring for 5 minutes, di-tert-butyl dicarbonate (4.35 g, 2 eq.) was added in small portions followed by sodium carbonate (4.20 g, 4 eq.). The reaction was stirred at room temperature for 24 hours before evaporating the solvents under reduced pressure. The residue was dissolved in 10percent aqueous sodium hydrogen carbonate solution (50 mL), washed with diethyl ether (3 x 20 mL) and citric acid was added until pH 4.0 was reached. The product was extracted with ethyl acetate (3 x 100 mL) and the combined organic phases were dried over magnesium sulfate, filtered and evaporated to give pure 4-tert-butoxy-2-(tert-butoxycarbonylamino)-4-oxobutanoic acid 5a as a colourless oil (2.82 g, 97percent).
97%	With sodium carbonate In tetrahydrofuran; water	(2R)-2-(tert-Butoxycarbonylamino)-4-tert-butoxy-4-oxo-butanoic acid is commercially available. The compound was prepared from commercial H-D-Asp(O Bu)-OH (25.0 g, 132 mmol), Boc₂0 (57.7 g, 264 mmol), and anhydrous sodium carbonate (Na₂C0₃) (55.5 g, 529 mmol) in a mixture of tetrahydrofuran (265 mL) and distilled water (160 mL) (37.1 g, 97percent yield) (Henry, et al., Bioorg. Med. Chem. Lett., 2012, 22(15), 4975-4978; Ollivier, et al., Tetrahedron Lett., 2010, 51, 4147-4149). Colorless solid. M.p.: 47-53 °C. 1H MR (300 MHz, CDC1₃): δ 7.2-6.6 (br. s, 1H), 5.52 (d, J= 8.7 Hz, 1H), 4.62-4.50 (m, 1H), 2.94 (dd, J= 16.8, 4.2 Hz, 1H), 2.74 (dd, J= 16.8, 4.8 Hz, 1H), 1.45 (s, 9H, partially superimposed), 1.44 (s, 9H, partially superimposed) ppm. LC/MS: R_t = 1.645 min; ESI (pos.): mlz = 290.20 (M+H⁺)⁺, 601.00 (2M+Na⁺)⁺; ESI (neg.): mlz = 288.10 (M-H⁺)^", 576.90 (2M-H⁺)^~. The analytical data correspond to the analytical data obtained for the (S)- enantiomer in Example 6.

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 15, p. 4975 - 4978
[2] Patent: WO2017/24009, 2017, A1, . Location in patent: Paragraph 0637

[ 155542-33-9 ] Synthesis Path-Downstream 1~31

1
[ 6066-82-6 ]
[ 155542-33-9 ]
(R)-4-tert-butyl 1-(2,5-dioxopyrrolidin-1-yl)-2-(tert-butoxycarbonylamino)succinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69%	With dicyclohexyl-carbodiimide; In ethyl acetate;	<strong>[155542-33-9](R)-4-tert-butoxy-2-(tert-butoxycarbonylamino)-4-oxobutanoic acid</strong> (5 g,17.3 mmol) and N-hydroxysuccinimide (2.18 g, 19.0 mmol) were dissolved into ethyl acetate (20 mL). N,N'-Dicyclohexylcarbodiimide (3.91 g, 19.0 mmol) was dissolved into ethyl acetate (10 mL) and added dropwise to the solution. The mixture was stirred overnight, filtered and concentrated to dryness. The residue was taken up into methylene chloride (200 mL) and washed with saturated sodium bicarbonate (2 x 25 mL) and brine (25 mL), dried over MgSO4, and concentrated to dryness to give the title compound (4.6 g, 69%) as a clear oil.

Reference： [1]Patent: WO2008/109991,2008,A1 .Location in patent: Page/Page column 78

2
[ 155542-33-9 ]
[ 957204-07-8 ]
[ 957204-08-9 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 14h;	TEA (0.697 mL) was added at room temperature to a DMF solution (4 mL) of 5-[3,5-bis-(trifluoromethyl)benzyloxy]indoline hydrochloride (398 mg), <strong>[155542-33-9]Boc-D-Asp(OtBu)-OH</strong> (289 mg), EDC·HCl (288 mg), and HOBt (203 mg), and the mixture was stirred at room temperature 14 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel flash column chromatography (Biotage 25S), to thereby yield the title compound (566 mg). NMR(CDCl3)delta: 1.42(9H,s),1.43(9H,s),2.58(1H,dd,J=15.7,5.9Hz),2.83(1H,dd,J=1 5.7,7.8Hz),3.20(2H,t,J=7.8Hz),4.25-4.43(2H,m),4.92(1H,dd,J=15.2,6.6Hz),5.13(2H,s),5.28(1H,d,J=9. 6Hz),6.80(1H,dd,J=8.8,2.7Hz),6.85(1H,d,J=2.5Hz),7.84(2H,s),7. 89(1H,s),8.15(1H,d,J=8.8Hz). MS(ESI)m/z:633(M+H)+.

Reference： [1]Patent: EP2017263,2009,A1 .Location in patent: Page/Page column 53-54

3
[ 155542-33-9 ]
[ 957204-17-0 ]
[ 957204-19-2 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide;	<strong>[155542-33-9]Boc-D-Asp(OtBu)-OH</strong> (205 mg), HOBt (120 mg), EDC·HCl (170 mg), and TEA (413 muL) were added to a DMF solution (10 mL) of 5-(2-cyanobiphenyl-4-ylmethoxy)indoline hydrochloride (215 mg), and the mixture was stirred overnight. To the reaction mixture, saturated aqueous sodium bicarbonate solution was added, followed by extracting twice, each with ethyl acetate. The extracts were combined and washed with saturated brine, followed by drying over sodium sulfate anhydrate and concentrating. The residue was purified by flash column chromatography (Yamazen Hi-Flash column L), to thereby yield the title compound (327 mg). NMR(CDCl3)delta: 1.42(9H,s),1.43(9H,s),2.58(1H,dd,J=6.1,15.7),2.80-2.86(1H,m),3.21(2H,t,J=8.3Hz),4.28-4.41(2H,m),4.89-4.95(1H,m),5.10(2H,s),5.27(1H,d,J=9.8Hz),6.78-6.85(2H,m),7.43-7.58(6H,m),7.69(1H,dd,J=1.7,8.1Hz),7.83(1H,d,J=1.5Hz),8.14(1H ,d,J=8.8Hz). MS(ESI)m/z:598(M+H)+.

Reference： [1]Patent: EP2017263,2009,A1 .Location in patent: Page/Page column 58

4
[ 155542-33-9 ]
[ 957204-25-0 ]
[ 957204-26-1 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 14h;	TEA (0.157 mL) was added at room temperature to a DMF solution (2 mL) of 5-[(1-phenyl-5-trifluoromethyl-1H-pyrazol-3-yl)methoxy]indoline hydrochloride (89 mg), <strong>[155542-33-9]Boc-D-Asp(OtBu)-OH</strong> (65.1 mg), EDC·HCl (64.7 mg), and HOBt (45.6 mg), and the mixture was stirred at room temperature for 14 hours. The resultant mixture was concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (Biotage 25S), to thereby yield the title compound (85.0 mg). NMR(CDCl3)delta: 1.42(9H,s),1.43(9H,s),2.58(1H,dd,J=15.6,5.9Hz),2.83(1H,q,J=7. 7Hz),3.20(2H,t,J=8.4Hz),4.26-4.47(1H,m),4.88-4.98(1H,m),5.12(3H,s),5.28(1H,d,J=9.0Hz),6.78-6.96(3H,m),7.47-7.51(5H,m),8.13(1H,d,J=8.8Hz). MS (ESI) m/z : 631 (M+H) +.

Reference： [1]Patent: EP2017263,2009,A1 .Location in patent: Page/Page column 64-65

5
[ 155542-33-9 ]
[ 957204-28-3 ]
[ 957204-29-4 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide;	<strong>[155542-33-9]Boc-D-Asp(OtBu)-OH</strong> (181 mg), HOBt (106 mg), EDC-HCl (150 mg), and TEA (364 muL) were added to a DMF solution (10 mL) of 5-(2-nitro-4-biphenylmethoxy)indoline hydrochloride (200 mg), and the mixture was stirred overnight. To the reaction mixture, saturated aqueous sodium bicarbonate solution was added, followed by extraction twice, each with ethyl acetate. The extracts were combined and washed with saturated brine, followed by drying over sodium sulfate anhydrate and concentrating. The residue was purified by flash column chromatography (Yamazen Hi-Flash column L), to thereby yield the title compound (309 mg). NMR (CDCl3 ) delta : 1.42(9H,s), 1.43(9H,s), 2.58(1H,dd,J=6.1,15.7Hz), 2.83(1H,dd,J=7 , 8,15.7Hz), 3.21(2H,t,J=8.3Hz), 4.30-4.39(2H,m), 4.89-4.95(1H,m), 5.14(2H,s), 5.27(1H,d,J=9.3Hz), 6.79-6.86(2H,m),7.26-7.47(6H,m), 7.66(1H,dd,J=1.3,8.0Hz), 7.93(1H,d,J=1.3Hz), 8.14(1H ,d,J=8.8Hz). MS (ESI) m/z : 618 (M+H)+.

Reference： [1]Patent: EP2017263,2009,A1 .Location in patent: Page/Page column 68

6
[ 155542-33-9 ]
[ 957204-42-1 ]
[ 957204-43-2 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; for 15h;	EDC·HCl (63.0 mg), HOBt (44.5 mg), and TEA (0.152 mL) were added at room temperature to a suspension of 5-[2-(4-phenyl-5-trifluormethyl-2-thienyl)ethyl]indoline hydrochloride (100 mg) and <strong>[155542-33-9]Boc-D-Asp(OtBu)-OH</strong> (70.0 mg) in DMF (3.0 mL), and the mixture was stirred for 15 hours. The reaction mixture was concentrated under reduced pressure, and to the concentrate, ethyl acetate (30 mL), saturated aqueous sodium hydrogencarbonate solution (20 mL), and water (40 mL) were added for phase separation. The aqueous layer was extracted with ethyl acetate (20 mL). The extracts were combined and dried with sodium sulfate anhydrate. Solvent was removed under reduced pressure. The residue was purified by preparative silica gel thin-layer chromatography, to thereby yield the title compound (33.7 mg). The compound was employed in a subsequent reaction without further purification. NMR (CDCl3) delta: 1.42(9H,s), 1.43(9H,s), 2.58(1H,dd,J=15.6,5.9Hz), 2.83(1H,dd,J=1 5.6,7.3Hz), 2.97(2H,t,J=7.6Hz), 3.11(2H,t,J=7.6Hz), 3.20(2H,t,J= 8.3Hz), 4.26-4.42(2H,m), 4.87-4.98(1H,m),5.27(1H,d,J=9.5Hz), 6.67(1H,s), 7.01-7.07 (2H,m), 7.30-7.42 (5H,m) , 8.12 (1H,d,J=7.8Hz). MS(ESI)m/z:533(M+H-isobutene×2)+.

Reference： [1]Patent: EP2017263,2009,A1 .Location in patent: Page/Page column 78-79

7
[ 155542-33-9 ]
[ 957204-46-5 ]
[ 957204-47-6 ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of <strong>[155542-33-9]Boc-D-Asp(OtBu)-OH</strong> (106 mg) in DMF (2 mL), DIEA (59 muL), HOBt (64.1 mg), and EDC·HCl (90.9 mg) were added at room temperature, and the reaction mixture was stirred for 10 minutes. A solution of 7-[(4-phenyl-5-trifluoromethyl-2-thienyl)methoxy]-2,3-dihydrobenzo[1,4]oxazine hydrochloride (156 mg) and DIEA (100 muL) in DMF (1 mL) was added thereto at room temperature, followed by stirring for 14 hours. The reaction mixture was concentrated under reduced pressure, and chloroform (10 mL) and water (5 mL) were added for phase separation. The aqueous layer was extracted with chloroform (5 mL x 3). The extracts were combined and dried over sodium sulfate anhydrate. Solvent was removed under reduced pressure. The residue was purified by silica gel flash column chromatography (Biotage 25S), to thereby yield the title compound (73.4 mg). NMR (CDCl3) delta : 1.46-1.39(20H,m),3.70(1H,s),4.40-4.22(3H,m),5.18(2H,s),5.37(1H,d,J=9.02Hz),6.60-6.51(2H,m),7.07(1H,s),7.44-7.38(6H,m).

Reference： [1]Patent: EP2017263,2009,A1 .Location in patent: Page/Page column 82

8
[ 155542-33-9 ]
[ 957207-46-4 ]
[ 957204-60-3 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; for 48h;	TEA (0.35 mL) was added at room temperature to a DMF solution (5 mL) of 5-[(4-cyclohexyl-2-trifluoromethylphenyl)methoxy]indoline hydrochloride (0.21 g), <strong>[155542-33-9]Boc-D-Asp(OtBu)-OH</strong> (Watanabe Chemical Industries, Ltd.) (0.14 g), EDC-HCl (0.14 g), and HOBt (0.10 g), and the mixture was stirred for 2 days hours. The reaction mixture was concentrated, and the residue was purified by silica gel flash column chromatography (Biotage 25S), to thereby yield the title compound (0.37 g). 1H-NMR (CDCl3) delta: 1.11-1.48(20H,m), 1.59-1.69(2H,m), 1.71-1.80(1H,m), 1.81-1.93 (5H,m), 2.47-2.67 (2H,m), 2.75-2.88 (1H,m), 3.10-3.26(2H,m),4.19-4.40(2H,m),4.81-4.99(1H,m), 5.18(2H,s), 5.29(1H, d, J=10.0Hz), 6.91-6.64(2H,m), 7.38(1H,d,J=8.1Hz), 7.45-7.54(1H,m), 7.60-7.73(1H,m), 8.11(1H, d, J=8.8Hz). MS (ESI) m/z : 647 (M+H)+.

Reference： [1]Patent: EP2017263,2009,A1 .Location in patent: Page/Page column 96-97

9
[ 155542-33-9 ]
[ 957204-63-6 ]
[ 957204-64-7 ]

Yield	Reaction Conditions	Operation in experiment
		To 1-(tert-butoxycarbonyl)-5-(4-cyclohexylmethoxyphenyl)indoline (459 mg), 4N HCl/1,4-dioxane (10 mL) was added, and the mixture was stirred for 3 hours, followed by concentration. Subsequently, Boc-D-Asp(OBu-t)-OH (326 mg), EDC·HCl (324 mg), HOBt (228 mg), TEA (471 muL), and DMF (10 mL) were added thereto, followed by stirring for 12 hours. The reaction mixture was extracted with ethyl acetate (200 mL), and the extract was washed with saturated brine (2 x 100 mL), followed by drying over sodium sulfate anhydrate. Solvent was evaporated, and the residue was purified by silica gel column chromatography (Yamazen Hi-Flash column 3L), to thereby yield the title compound (400 mg). 1H-NMR (CDCl3) delta : 1.06(2H, ddd, J=23.62,12.15,2.99Hz), 1.15-1.38(4H,m), 1.41-1.45(18H,m),1.66-1.93(4H,m), 2.59(1H, dd, J=15.8,6.0Hz),2.85(1H, dd, J=15.9,7.6Hz), 3.26(2H,t,J=8.3Hz), 3.79(2H, d, J=6.8Hz), 4.29-4.48(2H,m), 4.95(1H, q, J=7.6Hz), 5.27-5.33 (1H,m), 6.92-6.96(2H,m), 7.36-7.40(2H,m), 7.44-7.49(2H,m), 8.24-8.19(1H,m). 1H on the indoline benzene ring not observed.

Reference： [1]Patent: EP2017263,2009,A1 .Location in patent: Page/Page column 99-100

10
[ 155542-33-9 ]
[ 957204-65-8 ]
[ 957204-66-9 ]

Yield	Reaction Conditions	Operation in experiment
		To 5-(4-benzyloxyphenyl)-1-(tert-butoxycarbonyl)indoline (446 mg), 4N HCl/1,4-dioxane (10 mL) was added, and the mixture was stirred for 3 hours, followed by concentration. Subsequently, Boc-D-Asp(OBu-t)-OH (387 mg), EDC·HCl (319 mg), HOBt (225 mg), TEA (464 muL), and DMF (10 mL) were added thereto, followed by stirring for 12 hours. The reaction mixture was extracted with ethyl acetate (200 mL). The extract was washed with saturated brine (2 x 100 mL) and dried over sodium sulfate anhydrate. Solvent was evaporated, and the residue was purified by silica gel column chromatography (Yamazen Hi-Flash column 3L), to thereby yield the title compound (198 mg). 1H-NMR (CDCl3) delta: 1.41-1.45(18H,m), 2.59(1H, dd, J=16.1,6.3Hz), 2.85(1H, dd, J=15.9, 7.6Hz) 3.26(2H, t, J=8.5Hz), 4.28-4.45(2H,m), 4.90-5.00(1H,m), 5.08-5.14(2H,m), 5.26-5.33(1H,m), 7.05-7.00(2H,m), 7.50-7.30(9H,m),8.22(1H, d, J=8.8Hz). MS (ESI) m/z : 573 (M+H)+.

Reference： [1]Patent: EP2017263,2009,A1 .Location in patent: Page/Page column 101-102

11
[ 155542-33-9 ]
[ 957204-71-6 ]
[ 957204-72-7 ]

Yield	Reaction Conditions	Operation in experiment
		To 5-(4-benzyloxy-3-trifluoromethylbenzyloxy)-1-(tert-butoxycarbonyl)indoline (970 mg), 4N HCl/1,4-dioxane (20 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in DMF (20 mL). To the solution, <strong>[155542-33-9](2R)-[(tert-butoxycarbonyl)amino]succinic acid 4-tert-butyl ester</strong> (674 mg), HOBt (394 mg), EDC·HCl (558 mg), and TEA (1.35 mL) were added, followed by stirring overnight. To the reaction mixture, saturated aqueous sodium bicarbonate solution was added, and the resultant mixture was extracted twice with ethyl acetate. The extracts were combined and washed with saturated brine, followed by drying over sodium sulfate anhydrate. Insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (Yamazen Hi-Flash column 2L), to thereby yield the title compound (1.22 g). 1H-NMR (CDCl3) delta : 1.42(9H,s), 1.43(9H,s), 2.57(1H, dd, J=6.0,15.6Hz), 2.82(1H, dd, J=7 .5,15.6Hz),3.18(2H,t,J=8.3Hz),4.26-4.39(2H,m),4.90-4.97(3H,m),5.20-5.28(3H,m),6.76-6.81(2H,m), 7.03(1H, d, J=8.3Hz), 7.30-7.52(6H,m), 7.65(1H, d, J=2.0Hz), 8.12(1H, d, J=8.8Hz). MS (ESI) m/z : 671 (M+H)+.

Reference： [1]Patent: EP2017263,2009,A1 .Location in patent: Page/Page column 105-106

12
[ 155542-33-9 ]
[ 957204-73-8 ]
[ 957204-74-9 ]

Yield	Reaction Conditions	Operation in experiment
		To 1-(tert-butoxycarbonyl)-5-(4-phenethylbenzyloxy)indoline (290 mg, 0.675 mmol), 4N HCl/1,4-dioxane (15 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in DMF (15 mL). To the solution, <strong>[155542-33-9](2R)-[(tert-butoxycarbonyl)amino]succinic acid 4-tert-butyl ester</strong> (194 mg), HOBt (137 mg), EDC·HCl (194 mg), and TEA (471 muL) were added, and the mixture was stirred overnight at room temperature. To the reaction mixture, saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted twice with ethyl acetate. The extracts were combined and washed with saturated brine, followed by drying over sodium sulfate anhydrate. After filtration and concentration under reduced pressure, the residue was purified by flash column chromatography (Yamazen Hi-Flash column L), to thereby yield the title compound (365 mg). 1H-NMR (CDCl3 ) delta : 1.42(9H,s), 1.43(9H,s), 2.58(1H,dd,J=6.1,15.7Hz),2.83(1H,dd,J=7 .5,15.7Hz),2.91-3.00(4H,m),3.18(2H,t,J=8.3Hz),4.26-4.40(2H,m),4.93(3H,s), 5.29(1H,d,J=9.3Hz),6.76-6.81(2H,m),7.12-7.40(9H,m),8.12(1H,d,J=8.8Hz). MS (ESI)m/z:602 (M+2)+.

Reference： [1]Patent: EP2017263,2009,A1 .Location in patent: Page/Page column 108

13
[ 155542-33-9 ]
[ 92818-38-7 ]
[ 957204-75-0 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; for 15h;	EDC·HCl (490 mg), HOBt (345 mg), and TEA (1.48 mL) were added at room temperature to a suspension of 5-indolinol hydrochloride (413 mg) and Boc-D-Asp(OBu-tert)-OH (commercially available) (616 mg) in DMF (10 mL), and the mixture was stirred for 15 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel flash column chromatography (Biotage 40M), to thereby yield the title compound (406 mg). 1H-NMR (CDCl3) delta: 1.41(9H,s), 1.43(9H,s), 2.56(1H, dd, J=15.7,6.1Hz), 2.81(1H, dd, J=1 5.7,7.4Hz), 3.11(2H, t, J=8.3Hz), 4.20-4.36(2H,m), 4.85-4.93(1H,m), 5.04(1H,s), 5.29(1H, d, J=9.3Hz), 6.63(1H, d, J=8.5Hz), 6 .66(1H,s), 8.04 (1H, d, J=8.5Hz). MS (ESI) m/z : 407 (M+H)+.

Reference： [1]Patent: EP2017263,2009,A1 .Location in patent: Page/Page column 109-110

14
[ 155542-33-9 ]
[ 957204-22-7 ]
[ 957204-23-8 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 72h;	EDC·HCl (243 mg), HOBt (101 mg), and TEA (0.350 mL) were added at room temperature to a suspension of 5-[(2-trifluoromethyl-4-biphenyl)methoxy]indoline hydrochloride (342 mg) and <strong>[155542-33-9]Boc-D-Asp(OtBu)-OH</strong> (244 mg) in DMF (3.0 mL), and the mixture was stirred for 3 days. The reaction mixture was concentrated under reduced pressure. To the concentrate, ethyl acetate (30 mL), saturated aqueous sodium hydrogencarbonate solution (20 mL), and water (40 mL) were added for phase separation, and the aqueous layer was extracted with ethyl acetate (20 mL). The extracts were combined and dried over sodium sulfate anhydrate. Solvent was removed under reduced pressure. The residue was purified by silica gel flash column chromatography (Biotage 40M), to thereby yield the title compound (473 mg). NMR(CDCl3)delta: 1.42(9H,s)1.43(9H,s),2.58(1H,dd,J=15.6,6.1Hz),2.83(1H,dd,J=15 .6,7.6Hz),3.21(2H,t,J=8.4Hz),4.26-4.42(2H,m),4.88-4.98(1H,m),5.12(2H,s),5.27(1H,d,J=10.0Hz),6.83(1H,dd,J=8.7,2. 7Hz),6.87(1H,s),7.29-7.43(6H,m),7.62(1H,d,J=8.3Hz),7.80(1H,s)8.14(1H,d,J=8.8Hz). MS(ESI)m/z:641(M+H)+.

Reference： [1]Patent: EP2017263,2009,A1 .Location in patent: Page/Page column 61-62

15
[ 155542-33-9 ]
[ 957204-10-3 ]
[ 957204-11-4 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide;	<strong>[155542-33-9]Boc-D-Asp(OtBu)-OH</strong> (195 mg), HOBt (114 mg), EDC·HCl (161 mg), and TEA (392 muL) were added to a DMF solution (10 mL) of 5-(4-biphenylmethoxy)indoline hydrochloride (190 mg), and the mixture was stirred overnight. To the reaction mixture, saturated aqueous sodium bicarbonate solution was added, followed by extracting twice, each with ethyl acetate. The extracts were combined and washed with saturated brine, followed by drying over sodium sulfate anhydrate and concentrating. The residue was purified by flash column chromatography (Yamazen Hi-Flash column L), to thereby yield the title compound (321 mg). NMR(CDCl3)delta: 1.42(9H,s),1.43(9H,s),2.57(1H,dd,J=6.1,15.7Hz),2.79-2.85(1H,m),3.19(2H,t,J=8.3Hz),4.26-4.40(2H,m),4.89-4.95(1H,m),5.08(2H,s),5.28(1H,d,J=9.6Hz),6.81-6.85(2H,m),7.33-7.50(5H,m),7.58-7.62(4H,m),8.12(1H,d,J=8.6Hz). MS (ESI) m/z : 573 (M+H) +.

Reference： [1]Patent: EP2017263,2009,A1 .Location in patent: Page/Page column 55-56

16
[ 155542-33-9 ]
[ 957204-34-1 ]
[ 957204-35-2 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; for 12h;	6-[2-(4-Biphenyl)ethoxy]indoline hydrochloride (216 mg) and <strong>[155542-33-9]Boc-D-Asp(OtBu)-OH</strong> (213 mg) were dissolved in DMF (10 mL), and EDC·HCl (177 mg), HOBt (126 mg), and TEA (428 muL) were added to the solution, followed by stirring for 12 hours. The reaction mixture was diluted with ethyl acetate (200 mL). The organic layer was washed with saturated brine and dried over sodium sulfate anhydrate, and solvent was removed by evaporation. The residue was purified by silica gel flash column chromatography (Yamazen Hi-Flash L), to thereby yield the title compound (198 mg). NMR (CDCl3) delta: 1.37-1.46(18H,m),2.56 (1H,dd,J=15.62,6.10Hz), 2.82(1H,dd,J=15.87,8.06Hz), 3.07-3.17(4H,m),4.15-4.42(4H,m),4.92(1H,q,J=7.3Hz), 5.23(1H,d,J=9.0Hz), 6.62(1H,dd,J =8.3,2.4Hz), 7.05(1H,d,J=8.3Hz), 7.32-7.37(3H,m), 7.40-7.46(2H,m), 7.51-7.55(2H,m), 7.60-7.56(2H,m),7.91(1H,d,J=2.2Hz). MS (ESI) m/z : 587 (M+H)+.

Reference： [1]Patent: EP2017263,2009,A1 .Location in patent: Page/Page column 71-72

17
[ 155542-33-9 ]
[ 957204-38-5 ]
[ 957204-39-6 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; for 12h;	4-[2-(4-Biphenyl)ethoxy]indoline hydrochloride (320 mg) and Boc-D-Asp(O-tBu)-OH (316 mg) were dissolved in DMF (10 mL), and EDC·HCl (262 mg), HOBt (184 mg), and TEA (380 muL) were added to the solution, followed by stirring for 12 hours. The reaction mixture was diluted with ethyl acetate (200 mL). The organic layer was washed with saturated brine and dried over sodium sulfate anhydrate, and solvent was removed by evaporation. The residue was purified by silica gel flash column chromatography (Yamazen Hi-Flash L), to thereby yield the title compound (198 mg). NMR (CDCl3) delta: 1.41(9H,s),1.43(9H,s),2.56(1H,dd,J=15.9,5.9Hz),2.82(1H,dd,J=1 5.9,7.6Hz),3.07-3.15(4H,m),4.20-4.41(4H,m),4.87-4.97(1H,m),5.27-5.34(1H,m),6.59(1H,d,J=8.3Hz),7.14(1H,t,J=8.2Hz),7.31-7.37(3H,m),7.43(2H,t,J=7.3Hz),7.60-7.52(4H,m),7.81(1H,d,J=8.1Hz). MS (ESI) m/z : 587 (M+H)+.

Reference： [1]Patent: EP2017263,2009,A1 .Location in patent: Page/Page column 74

18
[ 155542-33-9 ]
[ 957204-69-2 ]
[ 957204-70-5 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; for 14h;	1- (tert-Butoxycarbonyl) -5- [3- (2, 4-difluorophenyl)propoxy]indoline hydrochloride (300 mg), Boc-D-Asp(O-tert-Bu)-OH (279 mg), EDC·HCl ( 265 mg), HOBt (187 mg), TEA (642 muL), and DMF (10 mL) were mixed together, and the mixture was stirred for 14 hours. The reaction mixture was extracted with ethyl acetate (200 mL). The extract was washed with saturated brine (2 x 100 mL) and dried over sodium sulfate anhydrate. Solvent was evaporated, and the residue was purified by silica gel column chromatography (Yamazen Hi-Flash column 2L), to thereby yield the title compound (493 mg). 1H-NMR (CDCl3) delta: 1.41-1.46(18H,m), 2.00-2.09(2H,m), 2.57(1H, dd, J=15.6,6.1Hz),2.75-2.86(3H,m), 3.18(2H, t, J=8.3Hz), 3.92(2H, t, J=6.2Hz), 4.25-4.40(2H,m),4.87-4.96(1H,m), 5.25-5.30(1H,m), 6.68-6.83(4H,m), 7.18-7.11(1H,m), 8.10(1H,d,J=8.8Hz). MS (ESI) m/z : 561 (M+H)+.

Reference： [1]Patent: EP2017263,2009,A1 .Location in patent: Page/Page column 103-104

19
[ 155542-33-9 ]
(R)-3-tert-butoxycarbonylamino-succinamic acid tert-butyl ester [ No CAS ]

Reference： [1]Tetrahedron,2009,vol. 65,p. 9536 - 9541

20
[ 155542-33-9 ]
[ 1393721-14-6 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 4975 - 4978

21
[ 155542-33-9 ]
[ 1393721-16-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 4975 - 4978

22
[ 155542-33-9 ]
[ 439150-76-2 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 4975 - 4978
[2]Patent: WO2008/109991,2008,A1

23
[ 155542-33-9 ]
[ 1393721-12-4 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 4975 - 4978

24
[ 155542-33-9 ]
[ 543-27-1 ]
C₁₈H₃₁NO₈ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: (S)-4-tert-Butoxy-2-(tert-butoxycarbonylamino)-4-oxobutanoic acid 5a (2.14 g, 7.4 mmol) was dissolved in dried THF (50 mL) and the solution was cooled to -30C before addition of N-methylmorpholine (0.82 mL, 1 eq.) and stirring for 10 min. i-Butyl chloroformate (0.98 mL, 1 eq.) was then added dropwise and the reaction warmed to -10C until the formation of the corresponding anhydride was found complete as shown by TLC. The solution was cooled again to -30C prior to addition of sodium borohydride (945 mg, 3 eq.) followed by MeOH (5 mL) drowise over 10 min. After 1 hour, the temperature was raised to 20C and the reaction left stirring for another hour before quenching with saturated ammonium chloride solution (50 mL). The THF was evaporated under reduced pressure and the aqueous layer extracted with Et2O (3 x 100 mL). The combined organic phases were dried over MgSO4, filtered and the filtrate evaporated to give the crude product which was purified by chromatography (SNAP-100 column, gradient elution using 10-100% EtOAc in n-hexane). Pure (S)-tert-butyl 3-(tert-butoxycarbonylamino)-4-hydroxybutanoate 6a was isolated as a white solid (1.85 g, 91%).

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 4975 - 4978

25
[ 24424-99-5 ]
[ 64960-75-4 ]
[ 155542-33-9 ]

Yield	Reaction Conditions	Operation in experiment
99%		General procedure: L-Aspartic acid 4-tert-butyl ester 4a (1.89 g, 10 mmol) was dissolved in a mixture of tetrahydrofuran (20 mL) and water (12 mL) at 0C. After stirring for 5 minutes, di-tert-butyl dicarbonate (4.35 g, 2 eq.) was added in small portions followed by sodium carbonate (4.20 g, 4 eq.). The reaction was stirred at room temperature for 24 hours before evaporating the solvents under reduced pressure. The residue was dissolved in 10% aqueous sodium hydrogen carbonate solution (50 mL), washed with diethyl ether (3 x 20 mL) and citric acid was added until pH 4.0 was reached. The product was extracted with ethyl acetate (3 x 100 mL) and the combined organic phases were dried over magnesium sulfate, filtered and evaporated to give pure 4-tert-butoxy-2-(tert-butoxycarbonylamino)-4-oxobutanoic acid 5a as a colourless oil (2.82 g, 97%).
97%	With sodium carbonate; In tetrahydrofuran; water;	(2R)-2-(tert-Butoxycarbonylamino)-4-tert-butoxy-4-oxo-butanoic acid is commercially available. The compound was prepared from commercial H-D-Asp(O Bu)-OH (25.0 g, 132 mmol), Boc20 (57.7 g, 264 mmol), and anhydrous sodium carbonate (Na2C03) (55.5 g, 529 mmol) in a mixture of tetrahydrofuran (265 mL) and distilled water (160 mL) (37.1 g, 97% yield) (Henry, et al., Bioorg. Med. Chem. Lett., 2012, 22(15), 4975-4978; Ollivier, et al., Tetrahedron Lett., 2010, 51, 4147-4149). Colorless solid. M.p.: 47-53 C. 1H MR (300 MHz, CDC13): delta 7.2-6.6 (br. s, 1H), 5.52 (d, J= 8.7 Hz, 1H), 4.62-4.50 (m, 1H), 2.94 (dd, J= 16.8, 4.2 Hz, 1H), 2.74 (dd, J= 16.8, 4.8 Hz, 1H), 1.45 (s, 9H, partially superimposed), 1.44 (s, 9H, partially superimposed) ppm. LC/MS: Rt = 1.645 min; ESI (pos.): mlz = 290.20 (M+H+)+, 601.00 (2M+Na+)+; ESI (neg.): mlz = 288.10 (M-H+)", 576.90 (2M-H+)~. The analytical data correspond to the analytical data obtained for the (S)- enantiomer in Example 6.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 4975 - 4978
[2]Patent: WO2017/24009,2017,A1 .Location in patent: Paragraph 0637

26
[ 155542-33-9 ]
tert-butyl 6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-((3,5-dimethyl-7-(2-(methylamino)ethoxy)adamantan-1-yl)methyl)-5-methyl-1H-pyrazol-4-yl)picolinate [ No CAS ]
3-{1-[(3-{2-[D-alpha-aspartyl(methyl)amino]ethoxy}-5,7-dimethyltricyclo[3.3.1.1³'⁷]dec-1-yl)methyl]-5-methyl-1H-pyrazol-4-yl}-6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]pyridine-2-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		[000626] A solution of Example 1.27.1 (0.074 g), 2-(3H-[l,2,3]triazolo[4,5-b]pyridin-3-yl)-l, 1,3,3- tetramethylisouronium hexafluorophosphate(V) (0.038 g), N,N-diisopropylethylamine (0.048 mL) and <strong>[155542-33-9](R)-4-(tert-butoxy)-2-((tert-butoxycarbonyl)amino)-4-oxobutanoic acid</strong> (0.029 g) in dichloromethane ( 1 mL) was stirred for 2 hours. Trifluoroacetic acid (0.5 mL) was added, and stirring was continued overnight. The reaction was concentrated, dissolved in N,N- dimethylformamide (1.5 mL) and water (0.5 mL), and purified by reverse phase HPLC using a Gilson system, eluting with 10-75% acetonitrile in water containing 0.1% v/v trifluoroacetic acid. The desired fractions were combined and freeze-dried to provide the title compound. NMR (500 MHz, dimethyl sulfoxide-^) delta ppm 12.88 (s, IH), 8.16 (s, 3H), 8.04 (d, IH), 7.80 (d, IH), 7.62 (d, IH), 7.55-7.42 (m, 3H), 7.41-7.33 (m, 2H), 7.33-7.27 (m, IH), 6.96 (d, IH), 4.96 (s, 2H), 4.63-4.49 (m, IH), 3.89 (t, 2H), 3.82 (s, 2H), 3.61-3.37 (m, 4H), 3.10-2.97 (m, 4H), 2.89-2.73 (m, 2H), 2.67-2.52 (m, IH), 2.10 (s, 3H), 1.45-0.95 (m, 12H), 0.85 (s, 6H). MS (ESI) m/e 875.3 (M+H)+.
		A solution of Example 1.27.1 (0.074 g), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3- tetramethylisouronium hexafluorophosphate(V) (0.038 g), N,N-diisopropylethylamine (0.048 mL) and <strong>[155542-33-9](R)-4-(tert-butoxy)-2-((tert-butoxycarbonyl)amino)-4-oxobutanoic acid</strong> (0.029 g) in dichloromethane (1 mL) was stirred for 2 hours. Trifluoroacetic acid (0.5 mL) was added, and stirring was continued overnight. The reaction was concentrated, dissolved in N,N-dimethylformamide (1.5 mL) and water (0.5 mL), and purified by reverse phase HPLC using a Gilson system, eluting with 10- 75% acetonitrile in water containing 0.1% v/v trifluoroacetic acid. The desired fractions were combined and freeze-dried to provide the title compound. 1H NMR (500 MHz, dimethyl sulfoxide-d6) delta ppm 12.88 (s, 1H), 8.16 (s, 3H), 8.04 (d, 1H), 7.80 (d, 1H), 7.62 (d, 1H), 7.55-7.42 (m, 3H), 7.41- 7.33 (m, 2H), 7.33-7.27 (m, 1H), 6.96 (d, 1H), 4.96 (s, 2H), 4.63-4.49 (m, 1H), 3.89 (t, 2H), 3.82 (s, 2H), 3.61-3.37 (m, 4H), 3.10-2.97 (m, 4H), 2.89-2.73 (m, 2H), 2.67-2.52 (m, 1H), 2.10 (s, 3H), 1.45- 0.95 (m, 12H), 0.85 (s, 6H). MS (ESI) m/e 875.3 (M+H)+.
		A solution of Example 1.27 .1 (0.07 4 g), 2-(3H -[ 1 ,2,3 ]triazolo[ 4,5-b ]pyridin-3-yl)-1 ,1 ,3,3-tetramethylisouronium hexafluorophosphate(V) (0.038 g), N,N-diisopropylethylamine (0.048 mL)and <strong>[155542-33-9](R)-4-(tert-butoxy)-2-((tert-butoxycarbonyl)amino)-4-oxobutanoic acid</strong> (0.029 g) indichloromethane (1 mL) was stirred for 2 hours. Trifluoroacetic acid (0.5 mL) was added, andstirring was continued overnight. The reaction was concentrated, dissolved in N,N-10 dimethylformamide (1.5 mL) and water (0.5 mL), and purified by reverse phase HPLC using a Gilsonsystem, eluting with 10-75% acetonitrile in water containing 0.1% v/v trifluoroacetic acid. Thedesired fractions were combined and freeze-dried to provide the title compound. 1H NMR (500 MHz,dimethyl sulfoxide-d6) 8 ppm 12.88 (s, 1H), 8.16 (s, 3H), 8.04 (d, 1H), 7.80 (d, 1H), 7.62 (d, 1H),7.55-7.42 (m, 3H), 7.41-7.33 (m, 2H), 7.33-7.27 (m, 1H), 6.96 (d, 1H), 4.96 (s, 2H), 4.63-4.49 (m,15 1H), 3.89 (t, 2H), 3.82 (s, 2H), 3.61-3.37 (m, 4H), 3.10-2.97 (m, 4H), 2.89-2.73 (m, 2H), 2.67-2.52(m, 1H), 2.10 (s, 3H), 1.45-0.95 (m, 12H), 0.85 (s, 6H). MS (ESI) m/e 875.3 (M+Ht.

A solution of Example 1.27.1 (0.074 g), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.038 g), N,N-diisopropylethylamine (0.048 mL) and <strong>[155542-33-9](R)-4-(tert-butoxy)-2-((tert-butoxycarbonyl)amino)-4-oxobutanoic acid</strong> (0.029 g) in dichloromethane (1 mL) was stirred for 2 hours. Trifluoroacetic acid (0.5 mL) was added, and stirring was continued overnight. The reaction was concentrated, dissolved in N,N-dimethylformamide (1.5 mL) and water (0.5 mL), and purified by reverse phase HPLC using a Gilson system, eluting with 10-75% acetonitrile in water containing 0.1% v/v trifluoroacetic acid. The desired fractions were combined and freeze-dried to provide the title compound. 1H NMR (500 MHz, dimethyl sulfoxide-d6) 6 ppm 12.88 (s, 1H), 8.16 (s, 3H), 8.04 (d, 1H), 7.80 (d, 1H), 7.62 (d, 1H), 7.55-7.42 (m, 3H), 7.41-7.33 (m, 2H), 7.33-7.27 (m, 1H), 6.96 (d, 1H), 4.96 (s, 2H), 4.63-4.49 (m, 1H), 3.89 (t, 2H), 3.82 (s, 2H), 3.61-3.37 (m, 4H), 3.10-2.97 (m, 4H), 2.89-2.73 (m, 2H), 2.67-2.52 (m, 1H), 2.10 (s, 3H), 1.45- 0.95 (m, 12H), 0.85 (s, 6H). MS (ESI) m/e 875.3 (M+H)+.

Reference： [1]Patent: WO2016/94509,2016,A1 .Location in patent: Paragraph 000626
[2]Patent: WO2017/214462,2017,A2 .Location in patent: Page/Page column 457-458
[3]Patent: WO2017/214282,2017,A1 .Location in patent: Page/Page column 414
[4]Patent: US2017/355769,2017,A1 .Location in patent: Paragraph 1604

27
[ 155542-33-9 ]
[ 99-55-8 ]
tert-butyl (3R)-3-(tert-butoxycarbonylamino)-4-[(2-methyl-5-nitrophenyl)amino]-4-oxobutanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 0 - 60℃;	Following the General Procedure of Description 20, tert-butyl (3 )-3-(tert- butoxycarbonylamino)-4-[(2-methyl-5-nitro-phenyl)amino]-4-oxo-butanoate (22a) was prepared from (2R)-4-tert-butoxy-2-(tert-butoxycarbonylamino)-4-oxo-butanoic acid (commercially available or see Example 5 (Variant B)) (1 16 mg, 0.4 mmol), 2-methyl-5- nitro-aniline (61 mg, 0.4 mmol), HATU (228 mg, 0.6 mmol), and DIPEA (210 uL, 155 mg, 1.2 mmol) in anhydrous DMF (1.5 mL) from 0 C? room temperature to 60 C for overnight. Aqueous work-up and purification by silica gel column chromatography using mixtures of ethyl acetate (EtOAc) and hexane (EtOAc/hexane = 1 :4, v/v? EtOAc/hexane = 1 :3, v/v) yielded 123 mg (73% yield) of the title compound (22a) as a dark yellow oil. Rf. -0.74 (EtOAc/Hxn = 1 :2, v/v). 1H MR (300 MHz, CDC13): delta 8.75 (br. s, 1H), 7.90 (dd, J = 8.1, 2.7 Hz, 1H), 7.49 (d, J = 2.4 Hz, 1H), 7.30 (d, J= 8.7 Hz, 1H), 5.97 (br. d, J= 6.9 Hz, 1H), 4.70-4.55 (m, 1H), 2.95 (dd, J = 17.1, 4.5 Hz, 1H), 2.71 (dd, J= 17.1, 6.6 Hz, 1H), 2.36 (s, 3H), 1.48 (s, 9H), 1.47 (s, 9H) ppm. LC/MS: Rt = 2.741 min; ESI (neg.) mlz = 422.0 (M-H+)".

Reference： [1]Patent: WO2017/24009,2017,A1 .Location in patent: Paragraph 0589; 0732

28
[ 186581-53-3 ]
[ 155542-33-9 ]
tert-butyl (3R)-3-(tert-butoxycarbonylamino)-5-diazo-4-oxopentanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%		General procedure: Part B: Adapting literature protocols (Podlech and Seebach, Liebigs Ann., 1995, 1217- 1228; Limbach, et al., Liebigs Ann., 2006, 89(7), 1427- 1441; Podlech and Seebach, Angew. Chem. Int. Ed. Engl., 1995, 34(4), 471-472; Muller, et al., Synthesis, 1998, (6), 837- 841); and Bartosz-Bechowski and Konopinska, J. Prakt. Chem., 1989, 331(3), 532-536), an N-protected amino acid derivative (10 mmol) is dissolved under a nitrogen atmosphere in anhydrous tetrahydrofuran (THF) and the solution is cooled to about -20C (dry ice/acetone bath). To the solution is added N-methylmorpholine (NMM) (13 mmol), followed by neat isobutyl chloroformate (12 mmol). The reaction mixture is stirred at about -20C for about 2 h, when an excess of (5-10 equivalents) of the freshly prepared ethereal solution of diazomethane is added. Optionally, the precipitated NMM hydrochloride (NMM HCl) is filtered off under a nitrogen atmosphere prior to diazotation and the solvent(s) are optionally exchanged to Et20, THF, dichloromethane (DCM), or mixtures of any of the forgoing. The reaction mixture is gradually warmed to room temperature and stirred for an additional 2 h. Excess diazomethane is quenched with a few drops of acetic acid (HO Ac). The solvents are removed under reduced pressure using a rotary evaporator. The residue is dissolved in a mixture of Et20 and ethyl acetate (EtOAc). Basic aqueous work-up with a saturated aqueous solution of sodium hydrogencarbonate (NaHC03) and silica gel column chromatography provides the diazoketonmes typically as light yellow solids.; Following the General Procedure of Description 12 (Part B), tert-butyl (3R)-3- (tert-butoxycarbonylamino)-5-diazo-4-oxo-pentanoate (28a) was prepared in three individual reactions (a), b) and c) from commercial (2R)-4-tert-butoxy-2-(tert-butoxycarbonylamino)-4- oxo-butanoic acid (<strong>[155542-33-9]Boc-D-Asp(OtBu)-OH</strong>) (a) 3.0 g, 10.4 mmol; b) 4.0 g, 13.8 mmol; c) 6.2 g, 21.5 mmol), N-methylmorpholine (NMM) (a) 2.3 mL, 2.12 g, 20.8 mmol; b) 3.0 mL, 2.76 mL, 27.6 mmol; c) 4.7 mL, 4.32 g, 43.0 mmol)), isobutyl chloroformate (a) 2.7 mL, 2.84 g, 20.8 mmol; b) 3.6 mL, 3.78 g, 27.8 mmol; c) 5.0 mL, 5.27 g, 38.7 mmol)) in anhydrous tetrahydrofuran (THF) (a) 20 mL), or anhydrous dichloromethane (DCM) (b) 40 mL; c) 50 mL) and about 16-38 mmol of diazomethane in etheral solution in mixtures of diethyl ether (Et20)/dichloromethane (DCM) at a) -20C, b) 0C; c) room temperature. Extractive aqueous work-up followed by silica gel column chromatography with ethyl acetate (EtOAc)/hexane mixtures, e.g., EtOAc/hexane = 3 :7, v/v or EtOAc/hexane = 1 :4, v/v) afforded a) 2.76 g (85% yield); b) 1.7 g (39% yield); c) 3.4 g (51% yield) of the target compound (28a) as a yellow oil. Rf. -0.66 (EtOAc/Hxn = 1 : 1, v/v). Rf. -0.33 (EtOAc/Hxn = 1 :4, v/v). 1H MR (300 MHz, CDC13): delta 5.66 (s, 1H), 5.62 (br. d, J= 4.8 Hz, 1H), 4.50-4.40 (m, 1H), 2.86 (dd, J = 16.8, 4.8 Hz, 1H), 2.59 (dd, J= 16.8, 5.1 Hz, 1H), 1.44 (s, 9H), 1.42 (s, 9H) ppm. LC/MS: Rt = 2.240 min; ESI (pos.) mlz = 336.10 (M+Na+)+.

Reference： [1]Patent: WO2017/24009,2017,A1 .Location in patent: Paragraph 0573; 0757

29
[ 155542-33-9 ]
(3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-amine [ No CAS ]
tert-butyl (R)-3-((tert-butoxycarbonyl)amino)-4-(((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)amino)-4-oxobutanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%	With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃;	Step A: tert-butyl (R)-3-((tert-butoxycarbonyl)amino)-4-(((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)amino)-4-oxobutanoate A solution of (3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-amine (Example 114; 200 mg, 0.390 mmol) and <strong>[155542-33-9](R)-4-(tert-butoxy)-2-((tert-butoxycarbonyl)amino)-4-oxobutanoic acid</strong> (113 mg, 0.390 mmol) in DMF (2 mL) was treated with HATU (222 mg, 0.584 mmol) and TEA (217 muL, 1.56 mmol). The mixture was stirred at rt overnight, then was partitioned between EtOAc (40 mL) and water (30 mL). The organic layer was washed sequentially with water (30 mL) and brine (30 mL), dried and concentrated. The residue was subjected to column chromatography on silica gel, eluting with EtOAc-hexanes (gradient from 0-100%) to give tert-butyl (R)-3-((tert-butoxycarbonyl)amino)-4-(((3R,3aS,9bS)-9b-((4-fluorophenyl)-sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)amino)-4-oxobutanoate as a white solid (225 mg, 74% yield). LCMS m/z 785.4 (M+H)+; HPLC tR 1.23 min (Method A). 1H NMR (500 MHz, DMSO-d6) delta 7.76 (br d, J=8.2 Hz, 1H), 7.63 (br d, J=8.5 Hz, 1H), 7.55-7.47 (m, 1H), 7.15 (br s, 3H), 6.92 (t, J=8.5 Hz, 2H), 5.71 (br d, J=8.7 Hz, 1H), 4.68-4.47 (m, 1H), 4.39-4.25 (m, 1H), 3.39-3.23 (m, 1H), 2.99 (br d, J=5.1 Hz, 1H), 2.81-2.64 (m, 2H), 2.54-2.45 (m, 1H), 2.43-2.33 (m, 1H), 2.20-2.02 (m, 3H), 1.53-1.46 (m, 18H), 1.35-1.28 (m, 2H).

Reference： [1]Patent: US2018/127368,2018,A1 .Location in patent: Paragraph 0595-0596

30
[ 155542-33-9 ]
[ 1059704-55-0 ]

Reference： [1]Patent: WO2008/109991,2008,A1

31
[ 155542-33-9 ]
C₁₆H₃₃N₂O₄⁽¹⁺⁾*I^(1-) [ No CAS ]

Reference： [1]Patent: WO2008/109991,2008,A1

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